FMI Cells from trophoblast organoids mimic placental cells invading the uterus during the early weeks of pregnancy. Credits: FMI/University of Cambridge (bright-field microscopy image, artificially colored)

January 25, 2024

‘Mini-placentas’ shed light on early events that are key for a successful pregnancy

The placenta provides oxygen and nutrients to a growing baby, but its early interactions with a mother’s uterus remain an enigma. Working with lab-grown versions of developing placentas, FMI researchers have shed light on some of the mechanisms underlying the earliest stages of gestation, which are crucial for a successful pregnancy. Understanding how the placenta develops and interacts with the inner lining of the womb may inform future treatments for conditions such as pre-eclampsia — a dangerous pregnancy complication that can put at risk both the mother and her baby’s health.

In the first weeks of gestation, the placenta — a temporary organ that supplies the fetus with nutrients and oxygen and disposes of waste — attaches to the wall of the mother’s uterus. Faulty interactions between the placenta and the uterus can lead to serious pregnancy complications such as pre-eclampsia, which results in high blood pressure and protein in the urine. If not treated, the condition can be fatal for the mother and baby.

Despite the key role of the placenta, the mechanisms underlying its development remain unknown. “In the past, studying the human placenta has been a challenge because of the lack of suitable model systems,” says Elisa Magistrati, a postdoctoral researcher in the lab of Margherita Turco, whose latest work reveals that, when it comes to placental and maternal cells, it takes two to tango.

To look at the early stages of placenta development, Turco and her team grew ‘mini-placentas’ in the lab. These organs in a dish, known as trophoblast organoids, mimic the key features of the human placenta.

Turco’s collaborators at the University of Cambridge previously showed that immune cells called uterine natural killer cells, which are found only in the mother’s womb, produce specific immune molecules that may influence the behavior of placental cells. In the new work, Turco’s team — in collaboration with Ashley Moffett at the University of Cambridge and Roser Vento-Tormo at the Wellcome Sanger Institute — added these immune molecules to trophoblast organoids and found that they promote the development of placental cells, thus contributing to the successful embedding of the placenta into the lining of the uterus.

The immune signal produced by uterine natural killer cells also appears to influence the expression of genes, some of which have been associated with pre-eclampsia, in the placental cells.

“The most important discovery is that there is a bidirectional communication between the placental cells from the embryo and the maternal cells — which are, in this case, immune cells,” Turco says. “It's such a fascinating process: these are two different tissues from two genetically distinct individuals, yet they work together.”

Using ‘mini-placentas’, researchers may now be able to investigate how pre-eclampsia and other serious pregnancy complications occur, Magistrati says. “It's really rewarding that we can finally answer some physiological questions that could not be explored before.”

Original publication:
Qian Li*^, Andrew Sharkey*, Megan Sheridan*, Elisa Magistrati*, Anna Arutyunyan, Oisin Huhn, Carmen Sancho-Serra, Holly Anderson, Naomi McGovern, Laura Esposito, Ridma Fernando, Lucy Gardner, Roser Vento-Tormo^, Margherita Yayoi Turco^, and Ashley Moffett^ Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy Cell Stem Cell (2024) Advance online publication
*co-first authors
^co-corresponding authors

FMI Cells from trophoblast organoids mimic placental cells invading the uterus during the early weeks of pregnancy. Credits: FMI/University of Cambridge (bright-field microscopy image, artificially colored)

About the FMI first author
Elisa Magistrati was born in Piacenza, Italy. After receiving a PhD in Molecular Oncology from Istituto Fondazione di Oncologia Molecolare in Milan, she joined the Turco group as a postdoc in October 2021. Her research focuses on the fundamental mechanisms of placenta development. In her free time, she enjoys reading and hiking.

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